Nature Aging: The model demonstrates how RNA splicing defects can lead to Alzheimer's disease

Researchers have puzzled the neurodegenerative disease Alzheimer's disease for decades, but treatments to stop or reverse the disease's effects on the brain remain
elusive.
Recently, researchers have created a mouse model of human disease that is closer to the previous model, adding an important link
to the puzzle.
The findings were published in
Nature Aging.

The researchers used their new model to discover how defects in RNA splicing contribute to neurodegeneration in Alzheimer's
disease.
RNA splicing is a process that
removes non-coding gene sequences and links protein coding sequences together.

Junmin Peng said: "RNA splicing is an important step
in transcription and translation.
This is especially important in the brain because we know that the brain has more cellular diversity than any other organ in the body, and splicing is thought to be an important process
for producing protein diversity.
”

Junmin Peng's previous work revealed a particular component of the RNA splicing mechanism, called U1 small ribonucleoprotein (snRNP), which produces aggregates
in the brains of Alzheimer's patients.
The U1 snRNP complex is essential
in RNA splicing.

Now, Junmin Peng and his team have demonstrated that dysfunction of U1 snRNP contributes to neurodegeneration, opening up new avenues
of research for Alzheimer's treatment.
Studies have found that RNA splicing dysfunction due to U1 snRNP pathology contributes to neurodegeneration
.

"Our previous work has shown that U1 snRNP is an aggregate in the brain that forms tangled structures, but this is only descriptive, and until now we did not understand the mechanism
of connection between this pathology and disease phenotype.
"

The unique model links RNA splicing defects to neuronal hyperexcitability

The researchers created an RNA splicing-deficient mouse model
called N40K-Tg.
When the scientists uncontrolled the splicing mechanism, they observed basic neurodegeneration, but they wanted to understand why
.

"Splicing machinery is so important that creating a model in the lab to study it is a real challenge
.
" "We were able to create a model of
stitching dysfunction that occurs only in neurons.
This model demonstrates that splicing dysfunction can lead to neuronal toxicity and cognitive impairment
.
”

Inhibiting neuronal activity prevents brain overexcitability
.
If scientists inhibit the activity of inhibitory neurons, the neurons become more active, but it leads to toxicity
.
The researchers found significant effects on synaptic proteins, particularly those
involved in inhibiting neuronal activity.

"Excitotoxicity is very important because it is already known in the field of Alzheimer's disease," Junmin Peng said
.
"Even 20-30 years ago, it was recognized that neurons became super excited, and now we find that splicing mechanisms may be responsible for
excitotoxicity in Alzheimer's patients.
"

RNA splicing defects and β-amyloid aggregation binding

One hallmark of Alzheimer's disease is the aggregation
of β-amyloid and tau proteins in the brain.
Peng's previous work revealed that U1 snRNP also forms aggregates in the brain, but scientists were unable to study the role of U1 snRNP function in disease until they developed a model
that perturbed U1 snRNP function leading to RNA splicing defects.

To understand how RNA splicing defects behave in the case of β-amyloid aggregation, the researchers crossed
their mouse model with the β-amyloid model.
Together, these two types of toxic attacks reshape the brain's transcriptome and proteome, unregulating synaptic proteins and accelerating cognitive decline
.

"From the initial behavior, to cell biology, to the present molecular mechanisms, we have described the potential contribution
of RNA splicing mechanisms to neuronal excitotoxicity in Alzheimer's disease.
"

This crossover mouse model is closer to Alzheimer's in humans than earlier models and may be useful
for future disease research.